Invented by Barbara Slusher, Jonathan Powell, Institute of Organic Chemistry and Biochemistry CAS, Johns Hopkins University
Metabolism is the set of chemical reactions that occur within cells to convert food into energy. When these processes are disrupted or altered, it can result in metabolic reprogramming disorders such as diabetes, obesity, metabolic syndrome, and certain types of cancer. These disorders have become a global health concern, affecting millions of people worldwide.
The market for methods of treatment for metabolic reprogramming disorders is driven by several factors. Firstly, the increasing prevalence of these disorders is a major driver. Sedentary lifestyles, unhealthy diets, and genetic predispositions contribute to the rising incidence of metabolic disorders, creating a need for effective treatments.
Additionally, advancements in medical research and technology have led to a better understanding of the underlying mechanisms of metabolic reprogramming disorders. This has paved the way for the development of innovative treatment methods and compositions that target specific metabolic pathways or molecular targets involved in these disorders.
The market for these treatments is diverse and encompasses various approaches. Pharmacological interventions, including small molecule drugs and biologics, are commonly used to modulate metabolic pathways and restore normal metabolic function. For example, drugs that target insulin resistance in diabetes or appetite regulation in obesity are widely prescribed.
In recent years, there has been a growing interest in the use of natural compounds and nutraceuticals as potential treatments for metabolic reprogramming disorders. These compounds, derived from plants or other natural sources, have shown promising results in preclinical and clinical studies. They offer the advantage of being perceived as safer alternatives to synthetic drugs, with potentially fewer side effects.
Furthermore, lifestyle interventions such as diet and exercise play a crucial role in managing metabolic reprogramming disorders. As a result, the market for personalized nutrition and fitness programs tailored to individuals with these disorders is also expanding. These programs often combine dietary modifications, physical activity recommendations, and behavioral support to optimize metabolic health.
The market for methods of treatment for metabolic reprogramming disorders and compositions is highly competitive, with numerous pharmaceutical and biotechnology companies actively engaged in research and development. Additionally, academic institutions and government agencies are investing in this field to advance scientific knowledge and develop novel therapies.
However, challenges remain in this market. The complex nature of metabolic reprogramming disorders requires a multifaceted approach to treatment, making it difficult to find a one-size-fits-all solution. Additionally, regulatory hurdles, high development costs, and the need for extensive clinical trials pose challenges to bringing new treatments to market.
In conclusion, the market for methods of treatment for metabolic reprogramming disorders and compositions is expanding rapidly due to the increasing prevalence of these disorders and advancements in medical research. The development of innovative pharmacological interventions, natural compounds, and personalized lifestyle programs offer hope for improved outcomes for individuals with metabolic reprogramming disorders. However, further research and investment are needed to overcome the challenges associated with developing effective treatments in this complex field.
The Institute of Organic Chemistry and Biochemistry CAS, Johns Hopkins University invention works as follows
The disclosure provides methods for treating a condition or disease in a patient that involves metabolically-reprogrammed cell whose activation or function, growth or proliferation or survival is dependent on an increased activity of one or more metabolic pathways, including glutamine metabolism, glucose synthesis and fatty acids synthesis. This includes administering to the patient a compound with formula (I) and the pharmaceutically acceptable salts of the compound, wherein the R1, R2, and R2? are defined in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).
Background for Methods of treatment for metabolic reprogramming disorders and compositions
Cells may, under certain conditions, undergo a switch in metabolic profile from one that requires less activity on certain metabolic pathways for the cell to meet its energy needs to another that requires more activity on those metabolic pathways or an increased activity on other metabolic pathways. Cells may, under certain circumstances, switch from oxidative to glycolytic phosphorylation. Although glycolysis produces less adenosine Triphosphate (ATP), it is believed that aerobic glycolysis allows the production of amino acids, nucleic acid and lipids. All of these are essential for proliferating (Vander Heiden, et. al. (2009) Science 324(5930):1029-1033). Otto Warburg first described this use of glycolysis when oxygen is present in cancer cells in 1956 (Warburg (1956), Science 124 (3215):269-270), and it was later found to be an important factor in activated T cell (Warburg et. al. (1958) [Metabolism in leukocytes]. Zeitschrift fur Naturforschung. Teil B: Chemie, Biochemie, Biophysik, Biologie 13B (8):515-516). These metabolically reprogrammed cell depend on increased activity of specific metabolic pathways such as those involved in glycolysis, glutamine metabolism and fatty acids synthesis. Specific inhibitors of enzymes within these metabolic pathways have not been effective, because they modulate multiple points in each metabolic pathway as the cell’s metabolism reprogrammed.
The practice will usually employ, unless indicated otherwise, conventional techniques in cell biology, cell cultures, molecular and transgenic biology (e.g. DNA), microbiology, immunology and RNA interference technology (RNAi), which are within the scope of the art. Ausubel F. et. al. (eds.) provide non-limiting descriptions of some of these techniques. Sambrook Russell and Sambrook’s Molecular Cloning, John Wiley & Sons N.Y. edition of December 2008. A Laboratory Manual. 3rd ed. Cold Spring Harbor Laboratory Press. Cold Spring Harbor. 2001. Harlow, E. & Lane, D. Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory Press. Cold Spring Harbor. 1988. Freshney, R. I. ‘Culture Of Animal Cells – A Manual of Basic Technology? 5th ed. John Wiley & Sons. Hoboken. N.J. 2005. Goodman and Gilman, The Pharmacological basis of Therapeutics, McGraw Hill 2005, Katzung B., provide non-limiting information on therapeutic agents and diseases in humans. (ed.) Basic and Clinical Pharmacology. McGraw-Hill/Appleton & Lange, 10th ed. 2006 or 11th Edition (July, 2009). McKusick V. A. Mendelian inheritance in man contains non-limiting information about genes and genetic disorders. A Catalog of Human Genes and Genetic Disorders. Baltimore: Johns Hopkins University Press. 1998 (12th Edition) or the online database, Online Mendelian inheritance in Man (OMIM?) which is more recent. McKusick Nathans Institute of Genetic Medicine at Johns Hopkins University, Baltimore, Md. National Center for Biotechnology Information (Bethesda) and National Library of Medicine, Bethesda. ), as of May 1, 2010, World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/ and in Online Mendelian Inheritance in Animals (OMIA), a database of genes, inherited disorders and traits in animal species (other than human and mouse), at http://omia.angis.org.au/contact.shtml.
The presently disclosed subject material provides, in one aspect, a method of treating a patient with a condition, disorder, or disease that involves metabolically-reprogrammed cell whose activation and function, growth and proliferation, and/or their survival depend on an increased activity of a metabolic pathway chosen from the group consisting if glutamine metabolism and glycolysis and fatty acids synthesis. This method comprises administering to the patient at least a metabolic reprogramming drug that decreases the activity of a metabolic
The presently disclosed subject material provides, in one aspect, a method of treating a patient with a condition, disorder, or disease that involves aberrant or excessive glutamine metabolic activity, aberrant or excessive glycolysis or aberrant or excessive fatty acids synthesis. This method includes administering to the patient at least one metabolism reprogramming drug that reduces the activity of at the least one metabolic pathway from the group consisting glutamine metabolic, glycolysis and fatty acids synthesis at a dose effective for treating the condition,
The presently disclosed subject material involves, in one aspect, the use of a metabolic reprogramming drug that decreases the activity of a metabolic pathway chosen from the group consisting glutamine metabolic pathways, glycolysis and fatty acids synthesis, for treating conditions, diseases, or disorders that involve (i) metabolically-reprogrammed cell whose activation and/or function, growth, proliferation, and/or survivability depend on an increased activity of a metabolic pathway that is selected from the list consisting
In one aspect, the subject matter disclosed herein provides a composition pharmaceutical comprising an effective quantity of one, two or three metabolic reprogramming drugs that reduce the activity of a metabolic pathway selected from a group consisting of glycolysis, glutamine metabolism and fatty acids synthesis and a pharmaceutically accepted carrier, diluent or excipient. In some embodiments, at least one other therapeutic agent is included in the pharmaceutical composition. This can be selected from the following group: cytotoxic, immunotherapeutic, immunosuppressant, radiotherapeutic, anti-inflammatory, or neuroprotective agents.
In particular embodiments, the methods or uses include administering to the patient at least two metabolic reprogramming drugs that reduce the activity of two metabolic pathways chosen from the group consisting glutamine metabolism and glycolysis or fatty acid syntheses in an effective amount to treat the disease or condition.
In particular embodiments, the method, or use, includes administering to the patient at least three metabolic reprogramming drugs that decrease activity in a different metabolic pathway selected from the group consisting glutamine metabolism (glutamine metabolism), glycolysis (glycolysis), and fatty acids synthesis, each in an effective amount to treat the disease or condition.
In particular embodiments, a metabolic reprogramming agents decreases glutamine metabolism. In certain embodiments, a metabolic reprogramming drug is a glutamine-antagonist. In certain embodiments, a metabolic reprogramming drug is a glutamine analogue that interferes with the glutamine metabolism pathway. In particular embodiments, at least one metabolic reprogramming agent is selected from the group consisting of acivicin (L-(alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid), azaserine, and 6-diazo-5-oxo-norleucine (DON), and 5-diazo-4-oxo-L-norvaline (L-DONV). In certain embodiments, a metabolic reprogramming drug is a prodrug that inhibits a glutamine metabolism pathway. In certain embodiments, one or more metabolic reprogramming agents are prodrugs of acivicin (also known as azaserine), DON and L-DONV. In certain embodiments, a metabolic reprogramming drug that decreases glutamine metabolism is a compound with formulas (I), (IIA), (IIB), and (III).
In particular embodiments, a metabolic reprogramming agents decreases glycolysis. In certain embodiments, a glucose analogue that inhibits hexokinase is at least one metabolic agent. In certain embodiments, at the least one metabolic reprogramming agents is 2-deoxy D-glucose.
In particular embodiments, a metabolic reprogramming agents increases fatty acid metabolism. In certain embodiments, a metabolic reprogramming drug is an activator for 5? AMPK activity. Metformin is at least one metabolic reprograming agent in particular embodiments.
In particular embodiments the condition, disorder, or disease is an immune disorder. In certain embodiments, the metabolically reprogrammed cell is immune cells. In certain embodiments, the disorder, condition, or disease is a neurological disorder. In certain embodiments, metabolically reprogrammed neurons are included in the cells. In certain embodiments, a condition, disease or disorder may be caused by or associated with CNS infection-induced inflammation. In certain embodiments, cereberal malaria is the condition, disorder, or disease. In certain embodiments, a condition, disease or disorder due to or associated CNS inflammation without an infection is described. In certain embodiments, amyotrophic lateral sclerosis is the condition, disorder, or disease. Alzheimer’s Disease is a particular embodiment of the disease or condition. Parkinson’s Disease is a condition, disease or disorder that appears in certain embodiments. In certain embodiments, Parkinson’s Disease is the disease or condition. In certain embodiments, ARDS is the condition, disorder, or disease. In certain embodiments, arthritis is the condition, disorder, or disease. Asthma is a condition, disease or disorder that can be found in certain embodiments. In certain embodiments, allograft rejecting during cell, organ, or tissue transplantation is the condition, disorder, or disease. In certain embodiments, the treatment, prevention, or delay of a transplant rejection is further achieved by transplanting a tissue, cell, or organ in the subject. In certain embodiments, the allograft cell, tissue or organ comprises an MHC mismatched (e.g. complete MHC match) allograft. In certain embodiments, the procedure also includes administering a sufficient amount of immunosuppressant to the subject. In certain embodiments, cerebral malaria is the disease or condition. In certain embodiments, lupus is the condition, disorder, or disease. Pneumonitis is a condition, disorder, or disease that may be present in certain embodiments. In certain embodiments, pulmonary fibrosis is the condition, disorder, or disease.
In particular embodiments, a condition, disease or disorder does not include multiple sclerosis. In certain embodiments, a condition, disease or disorder that is not an immune disorder such as multiple sclerosis.
In one aspect, the presently-disclosed subject matter provides a treatment method for ARDS, which involves administering to a subject a metabolic reprogramming drug that reduces glutamine metabolism at a dose effective in treating ARDS. The presently disclosed subject involves using an effective amount at least one metabolic reprogramming agents that decreases the glutamine metabolism in order to treat ARDS.
In one aspect, the currently disclosed subject matter is a method of treating arthritis in a patient in need, which involves administering to the patient at least one metabolic agent that reduces glutamine metabolism to an effective amount to treat arthritis. In one aspect, the currently disclosed subject matter involves using an effective amount at least of a metabolic reprogramming drug that decreases glutamine metabolism to treat arthritis in the subject.
In one aspect, the currently disclosed subject matter is a method of treating asthma in a patient who needs it. The method involves administering to the patient at least one metabolic agent that reduces glutamine metabolism, in an effective amount to treat asthma. The presently disclosed subject involves using an effective amount at least one metabolic agent that decreases the glutamine metabolism in order to treat asthma.
In one aspect, the presently-disclosed subject matter provides a treatment method for amyotrophic lateral sclerosis in a patient in need of it, which includes administering to the patient at least one metabolic reprogramming drug that decreases glutamine metabolites in an effective amount to treat ALS. The presently disclosed subject involves using an effective amount at least one metabolic reprogramming agents that decreases the glutamine metabolism in order to treat ALS.
In one aspect, the presently-disclosed subject matter provides a treatment method for Alzheimer’s Disease, which involves administering to a subject a metabolic reprogramming drug that reduces glutamine metabolism at a level effective in treating Alzheimer’s Disease. The presently disclosed subject material involves using an effective amount at least one metabolic agent that decreases the glutamine metabolism in order to treat Alzheimer’s Disease.
In one aspect, the currently disclosed subject matter is a method to treat cerebral malaria in a patient in need of it. The method involves administering to the patient at least one metabolic agent that reduces glutamine metabolism to a level effective in treating cerebral malaria. The presently disclosed subject involves using an effective amount at least one metabolic agent that decreases the glutamine metabolism in order to treat cerebral malaria in a needy subject.
The presently disclosed subject material provides, in one aspect, a method of preventing or delaying rejections during allograft transplantation on a patient in need. This method comprises administering, to a patient about to undergo or undergoing a cell tissue or organ, or to a patient who has undergone such a transplantation, at least one metabolic agent that reduces glutamine metabolism to an effective amount to prevent or delay rejections due to the transplanted cell tissue or organ. In some embodiments, the method comprises transplanting a tissue, cell or organ in the subject. In certain embodiments, the method also includes administering an immune-suppressant to the subject. The subject matter disclosed herein includes the use of a sufficient amount of atleast one metabolic reprogramming drug that reduces glutamine metabolism in order to prevent or delay the rejection of an allograft in a patient in need of it.
In one aspect, the currently disclosed subject matter is a method for treating lupus on a subject who needs it. The method involves administering to the patient at least one metabolic agent that reduces glutamine metabolism to a level effective in treating lupus. The presently disclosed material involves using an effective amount at least one metabolic reprogramming agents that decrease glutamine metabolism in order to treat lupus.
Click here to view the patent on Google Patents.
Leave a Reply